Temozolomide induces senescence but not apoptosis in human melanoma cells.

in British journal of cancer by N M Mhaidat, X D Zhang, J Allen, K A Avery-Kiejda, R J Scott, P Hersey

TLDR

  • The study investigates why some melanoma cells are resistant to temozolomide (TMZ), a drug used to treat melanoma. The study found that the resistance is due to a protein called O(6)-methylguanine-DNA methyl transferase (MGMT) and the status of a protein called p53. The study also found that the drug temozolomide is not very effective against melanoma because of a problem with a process called apoptosis, which is a way for cells to die. The study suggests that pifithrin-alpha, a drug that can help with apoptosis, could be used in combination with temozolomide to make it more effective against melanoma.

Abstract

Temozolomide (TMZ), a DNA alkylating agent used in the treatment of melanoma, is believed to mediate its effect by addition of a methyl group to the O(6) position of guanine in DNA. Resistance to the agent may be in part due to the activity of O(6)-methylguanine-DNA methyl transferase (MGMT). In the present study, we show that sensitivity of melanoma cells to TMZ was dependent on their p53 status and levels of MGMT. Analysis of the mechanisms underlying reduced viability showed no evidence for induction of apoptosis even though marked levels of apoptosis was seen in TK6 lymphoma cells. Sensitivity of melanoma cells was associated with p53-dependent G2/M cell cycle arrest and induction of senescence. To verify the role of p53, the assays were repeated in presence of pifithrin-alpha, an inhibitor of p53. This resulted in increased viability of melanoma cells with wild-type p53 and reversed G2/M cell cycle arrest. Paradoxically, apoptosis was increased in melanoma but decreased as expected in TK6 lymphoma cells. These results are consistent with the view that TMZ is relatively ineffective against melanoma due to defective apoptotic signalling resulting from activation of p53. The nature of the defects in apoptotic signalling remains to be explored.

Overview

  • The study investigates the sensitivity of melanoma cells to temozolomide (TMZ) and its dependence on p53 status and levels of O(6)-methylguanine-DNA methyl transferase (MGMT).
  • The methodology used includes analysis of the mechanisms underlying reduced viability in melanoma cells and the role of p53 in G2/M cell cycle arrest and induction of senescence. The study also verifies the role of p53 using pifithrin-alpha, an inhibitor of p53. The primary objective is to understand the defects in apoptotic signalling resulting from activation of p53 in melanoma cells and their impact on TMZ sensitivity.

Comparative Analysis & Findings

  • The study shows that sensitivity of melanoma cells to TMZ was dependent on their p53 status and levels of MGMT. Analysis of the mechanisms underlying reduced viability showed no evidence for induction of apoptosis even though marked levels of apoptosis was seen in TK6 lymphoma cells. Sensitivity of melanoma cells was associated with p53-dependent G2/M cell cycle arrest and induction of senescence. The study also verifies the role of p53 using pifithrin-alpha, an inhibitor of p53. The results are consistent with the view that TMZ is relatively ineffective against melanoma due to defective apoptotic signalling resulting from activation of p53.

Implications and Future Directions

  • The study highlights the importance of p53 status and MGMT levels in determining TMZ sensitivity in melanoma cells. The findings suggest that defects in apoptotic signalling resulting from activation of p53 may be a major contributor to TMZ resistance in melanoma. Future research could explore the nature of these defects and develop strategies to overcome them. The study also suggests that pifithrin-alpha could be used as a therapeutic agent in combination with TMZ to enhance its effectiveness in melanoma.
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